Connectivity of diagnostic technologies: improving surveillance and accelerating tuberculosis elimination

André, Emmanuel; Isaacs, Chris; Affolabi, Dissou; Alagna, Riccardo; Brockmann, Dirk; Jong, Bouke C. de; Cambau, Emmanuelle; Churchyard, Gavin J.; Cohen, Ted; Delmée, Michel; Delvenne, Jean‐Charles; Mustafa, Farhat; Habib, Ali; Holme, Petter; Keshavjee, Salmaan; Khan, Aamir; Lightfoot, P; Moore, David; Moreno, Yamir; Mundade, Yamuna; Pai, Madhukar; Patel, Sanjay; Nyaruhirira, Alaine Umubyeyi; Rocha, Luis E. C.; Takle, Jeff; Trébucq, A; Creswell, Jacob; Boehme, Catharina

doi:10.5588/ijtld.16.0015

Cited by 30 publications

(27 citation statements)

References 14 publications

(13 reference statements)

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“…This information is deemed useful for conducting research on Ultra data and could be practical in the field if export of the melt peak temperatures through the LIS port becomes feasible in future software updates, together with other raw data (e.g.wild-type and Mut melt probes associated with RR mutation). Export to connectivity solutions such as DataToCare (Savics, Belgium), GXAlert (SystemOne, USA), or C360 (Cepheid, USA), with possible integration into e-Health patient charts beyond tuberculosis diagnostics, allows to transform this data into usable information for the National TB Programs using a combination of unique patient ID and geographical information (9, 28). This may not only greatly benefit the remote resolution of discordant results to improve patient management, but also aids to build more systematic data on the prevalence and impact of heteroresistance on a programmatic level.…”

Section: Discussionmentioning

confidence: 99%

How well do routine molecular diagnostics detect rifampicin heteroresistance inMycobacterium tuberculosis?

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Cobelens

et al. 2019

Preprint

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Phone: 21 +32(0)33455345; Fax number: +32(0)32476333 22 2 ABSTRACT 23Rifampicin heteroresistance -where rifampicin-resistant and -susceptible tuberculosis bacilli 24 co-exist -may result in failed standard TB treatment and potential spread of rifampicin-25 resistant strains. Detection of rifampicin heteroresistance in routine rapid diagnostic tests 26 (RDTs) allows for patients to receive prompt and effective multidrug-resistant-TB treatment, 27 and may improve rifampicin-resistant TB control. 28 The limit of detection (LOD) of rifampicin heteroresistance for phenotypic drug susceptibility 29 testing by the proportion method is 1%, yet is insufficiently documented for RDTs. We 30 therefore aimed to determine, for the four RDTs (XpertMTB/RIF, XpertMTB/RIF Ultra, 31 GenotypeMTBDRplusv2.0, and GenoscholarNTM+MDRTBII), the LOD per probe and 32 mutation, validated by colony-forming-unit-counting and targeted deep sequencing 33 (Deeplex-MycTB). 34 We selected one rifampicin-susceptible and four rifampicin-resistant strains, with mutation 35 D435V, H445D, H445Y, and S450L respectively, mixed them in various proportions in 36 triplicate, tested them with each RDT, and determined the LODs per mutation type. MycTB revealed concordant proportions of the minority resistant variants in the mixtures. 38 The Deeplex-MycTB-validated-LODs ranged from 20-80% for XpertMTB/RIF, 20-70% for 39 Xpert Ultra, 5-10% for GenotypeMTBDRplusv2.0, and 1-10% for GenoscholarNTM+MTBII for 40 the different mutations. 41 Deeplex-MycTB, GenotypeMTBDRplusv2.0, and GenoscholarNTM+MDRTBII, provide explicit 42 information on rifampicin heteroresistance for the most frequently detected mutations. 43

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Section: Discussionmentioning

confidence: 99%

How well do routine molecular diagnostics detect rifampicin heteroresistance inMycobacterium tuberculosis?

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Cobelens

et al. 2019

Preprint

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“…Much has been learnt from the implementation of Xpert MTB/RIF as summarised in Table 2 and includes [66, 67] cost and forecast models [68, 69], program interfacing [70], socio-economic trends [71], and quality assessment [72]. Additional innovations, being reported for the first time for possible TB control (currently, developed for GeneXpert instruments), is remote connectivity [73, 74]. Cepheid’s C360 is a web-based software that remotely connects all instruments and centrally collects result run information.…”

Section: Who Endorsed Diagnostic Technologiesmentioning

confidence: 99%

Diagnosis of opportunistic infections

Scott

Silva

Boehme

et al. 2017

Current Opinion in HIV and AIDS

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Purpose of the review TB incidence has declined ~1.5% annually since 2000, but continued to affect 10.4 million individuals in 2015, with 1/3 remaining undiagnosed or under reported. The diagnosis of TB among those co-infected with HIV is challenging as TB remains the leading cause of death in such individuals. Accurate and rapid diagnosis of active TB will avert mortality in both adults and children, reduce transmission, and assist in timeous decisions for ART initiation. This review describes advances in diagnosing TB, especially among HIV co-infected individuals, highlights national program’s uptake, and impact on patient care. Recent Findings The TB diagnostic landscape has been transformed over the last 5 years. Molecular diagnostics such as Xpert MTB/RIF, which simultaneously detects M. tuberculosis resistance to rifampicin, has revolutionised TB control programs. WHO endorsed the use of Xpert MTB/RIF in 2010 for use in HIV/TB co-infected patients, and later in 2013 for use as the initial diagnostic test for all adults and children with signs and symptoms of pulmonary TB. Line probe assays (LPAs) are recommended for the detection of rifampicin and isoniazid resistance in sputum smear-positive specimens and mycobacterial cultures. A second-line line probe assay has been recommended for the diagnosis of extensively drug-resistant (XDR)-TB Assays such as the urine lateral flow(LF)-lipoarabinomannan(LAM), can be used at the point of care (POC) and have a niche role to supplement the diagnosis of TB in seriously ill HIV infected, hospitalized patients with low CD4<100cells/μl. Polyvalent platforms such as the m2000 (Abbott Molecular, IL, USA) and GeneXpert (Cepheid, CA, USA) offer potential for integration of HIV and TB testing services. While the Research and Development (R&D) pipeline appears to be rich at first glance, there are actually few leads for true POC tests that would allow for earlier TB diagnosis or rapid, comprehensive drug susceptibility testing, especially when considering the very high attrition rates observed between biomarker discovery and product market entry. Summary In this review, we describe diagnostic strategies specifically for HIV and TB co-infected individuals. Molecular diagnostics in particular within the past 5 years have revolutionized and “disrupted” this field. They lend themselves to integration of services with platforms capable of polyvalent testing. Impact on patient care is, however, still debatable. What has been highlighted is the need for health system strengthening and for true POC testing that can be used in active case finding.

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“…The deluge of data produced by XpertMTB/RIF (Cepheid) can help improve global rifampicin-resistant tuberculosis (RR-TB) control strategies through molecular epidemiological surveillance (1, 2). Recently, a new version of the test – Xpert Ultra (hereinafter called Ultra) was released (3).…”

Section: Introductionmentioning

confidence: 99%

Xpert Ultra can unambiguously identify specific rifampicin resistance-conferring mutations

Deun

Meehan

et al. 2018

Preprint

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Phone: +32(0)33455345 21 Fax number: +32(0)32476333 22 23 24 2 Introduction 25The deluge of data produced by XpertMTB/RIF (Cepheid) can help improve global 26 rifampicin-resistant tuberculosis (RR-TB) control strategies through molecular 27 epidemiological surveillance (1, 2). Recently, a new version of the test -Xpert Ultra 28 (hereinafter called Ultra) was released (3). Determining the relationship between RR-29 conferring rpoB mutations, Ultra probes, and melting temperature shifts (∆Tm)the 30 difference between mutant and wildtype melting temperaturesallows Ultra results to 31 be utilized for rapid detection of RR-TB strains and related underlying rpoB mutations. 32 Methods 33To validate the usefulness of Ultra results for predicting specific mutations, we analyzed 34 10 RS-TB and 107 RR-TB strains from the Belgian Coordinated Collections of 35Microorganisms 36 in the Institute of Tropical Medicine, Antwerp, Belgium. These strains harbor 36 unique 37 RR-conferring mutations determined by rpoB sequencing. 38 Results 39Overall, 31/32 (97%) mutations inside the Rifampicin Resistance Determining Region 40 (RRDR) were correctly identified by Ultra. Of concern, mutation His445Arg gave a "RIF 41Resistance INDERTERMINATE" result among 3/4 strains tested while it was reported as 42 RR in the initial validation study (3). The silent mutation Thr444Thr was not reported as 43 RR (Figure 1). The RR-conferring mutations on codons 170, 250, 299, 482, and 491 44 situated outside the RRDR were not detected. 45The probe reactions observed were largely in agreement with previous results (3) albeit 46 we noted that mutations Met434Val, Met434Thr and those in codon 435 were captured 47 only by probe rpoB2; Ser450Leu and Ser450Trp were captured by both probes rpoB3 48 3 and rpoB4a, His445Arg was captured only by probe rpoB3; and Lys446Gln was 49 captured only by probe rpoB4. 50All mutations except those in codon 450 were associated with a negative ∆Tm (Figure 51 2). The combination of ∆Tm values with the capturing probes enabled to differentiate 52 mutations in codons 428, 430, 431, 432, 434, 435, 441, 445, 446, and 452, including 53 disputed mutations (4) ( Table 1). Mutation Asp435Tyr was unambiguously distinguished 54 from Asp435Val through probe rpoB2|∆Tm|, while mutations Ser441Gln and Ser441Leu 55 were discriminated from the rest by|∆Tm| values of probes rpoB2 and rpoB3. Mutations 56 His445Asp and His445Tyr were distinguished from disputed mutations His445Leu and 57 His445Asn through probe rpoB3 |∆Tm|. Ser450Leu was distinguished from Ser450Trp 58 by probe rpoB4A |∆Tm| except for one strain with an outlier rpoB4A Tm of 70.9°C in 59 contrast to the other 13 strains with rpoB4A Tm of 73.3-73.8°C. The indeterminate result 60 associated with His445Arg may be caused by its |∆Tm|=1.8°C compared with |∆Tm| 61 typically exceeding 2°C for other mutations. 62 Conclusions 63Our findings confirm the ability of Ultra to unambiguously identify a wide range of RRDR 64 mutations. With the unprecedented roll-out of XpertMTB/RIF and asso...

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Connectivity of diagnostic technologies: improving surveillance and accelerating tuberculosis elimination

Cited by 30 publications

References 14 publications

How well do routine molecular diagnostics detect rifampicin heteroresistance inMycobacterium tuberculosis?

How well do routine molecular diagnostics detect rifampicin heteroresistance inMycobacterium tuberculosis?

Diagnosis of opportunistic infections

Xpert Ultra can unambiguously identify specific rifampicin resistance-conferring mutations

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